Among the thirteen human aquaporins (AQP0-AQP12) distributed within cells of the stomach, duodenum, pancreas, airways, lungs, salivary glands, sweat glands, eyes, lacrimal glands, and the inner ear, AQP5 has been implicated in Sjogren's disease and in cancers of the lung, pancreas, colon etc.. Defective trafficking of AQP5 was found responsible for Sjogren's disease which inflicts about 4 million people (mostly women) in the US. Overexpression of AQP5 was identified in promoting cell proliferation and inhibiting apoptosis. Meanwhile, high-resolution x-ray structure of AQP5 has recently been determined. AQP5 resembles other aquaporins in its tetrameric conformation and in its water pore structure formed by each protomer. However, it lacks the four-fold quasi-symmetry among its four protomers and it contains a lipid, PS6, in its central pore. In light of the existent in vtro studies of AQP5's functions and its crystal structure, the following questions stand out: How does the structure of AQP5 embedded in the cell membrane under physiological conditions deviate from its crystallographic form? Does PS6 gate or inhibit the central pore? What are the specificities of the lipid-AQP5 interaction? How does the protein respond to its environmental changes in pH? And how does it respond to chemical modifications to its residues? These questions on the structure-function correlations of AQP5 need to be answered before new drugs can be designed that specifically target this protein. Answering these questions requires conducting extensive in silico experiments in an innovated approach. Two all-atom model systems of AQP5 embedded in a patch of lipid bi- layer explicitly solvated in physiological saline will be investigated: One with PS6 in the central pore of AQP5 and one without. Three specific aims will be pursued: 1.Determine the roles of the lipid in the central pore and identify the mechanism of its gating or inhibiting action. 2. Identify the protein's mechanisms of biological functions and determine its response to environmental changes. 3. Quantify AQP5's response to chemical modifications and thus identify the mechanisms of signaling, gating, or inhibiting its physiological functions. Upon completion of the proposed research, a detailed understanding will be achieved about AQP5's structure- function correlations: AQP5's degree of accessibility for trafficking before and after phosphorylation at the selected sites, the affinity and specificit of binding a lipid in its central pore, and the mechanisms of inhibiting and gating its physiological functions. The knowledge so gained will positively impact on finding new medicines to prevent and control AQP5-related diseases.